Novel growth peptides derived from protein factors having molecular weights of about 22 and 45 kDa stimulate mitogenic activity of epithelial, but not fibroblastic cells, in particular, kidney epithelial cells.
Acute renal failure is a serious disease associated with high mortality for which no "real" treatment currently exists. Acute renal failure is defined as the abrupt disruption of previously normal kidney function. It is caused by a wide variety of mechanisms including circulatory failure (shock), vascular blockade, glomerulonephritis, and obstruction to urine flow. In addition it can occur following surgery, trauma, sepsis, or with certain medications, particularly antibiotics and anticancer agents.
In 1985 some 140,000 Americans were hospitalized with acute renal failure (see 1990 Long Range Plan). The average cost of treatment associated with these cases was over $9000. Based on the growth in the disease over the past several years and normal inflation, it was estimated that currently some 240,000 patients develop acute renal failure annually at a cost of over $10,000 per patient. That translated to a staggering total cost to the U.S. healthcare system of almost $2.5 billion per year.
TABLE 1 ______________________________________ AVERAGE COST PER HOSPITAL DISCHARGE FOR KIDNEY AND UROLOGIC DISEASES, UNITED STATES, 1985.sup.1 Number of Average Cost per Discharges Discharge ______________________________________ 1. Acute renal failure 139,134 $9,329 2. Chronic renal failure 395,066 9,249 3. Kidney disease of diabetes mellitus 96,731 6,819 4. Kidney cancer 47,384 6,145 5. Hypertensive renal disease 182,625 5,796 6. Other intrinsic/systemic diseases 79,683 5,061 7. Bladder cancer 125,108 4,758 8. Impotence 30,452 4,344 9. Prostate cancer 246,201 3,791 10. Testicular cancer 14,219 3,711 11. Benign prostatic hyperplasia 482,348 3,648 12. Polycystic kidney disease 44,155 3,213 13. Glomerulonephritis 79,531 3,135 14. Bladder disorders 342,211 3,064 15. Urinary stone disease 453,018 2,920 16. Urinary tract infection 1,583,309 2,549 17. Incontinence 162,574 2,547 18. Hematuria 173,495 2,375 19. Prostatitis 108,024 2,010 20. Obstructive uropathy.sup.2 397,074 1,842 21. Other genitourinary infections 147,215 1,339 22. Preeclampsia 139,000 1,025 23. Testicular dysfunction 7,019 950 ______________________________________ .sup.1 Includes payments to physicians. .sup.2 Includes vesicoureteral reflux. SOURCES: National Center for Health Statistics: National Hospital Discharge Survey i985 (all listed diagnoses). Department of Veterans Affairs, for year ending September 30, 1986 (firstlisted diagnoses) (unpublished). Health Care Financing Administration, Medicare provider analyses and review data 1985 (unpublished).
As can be seen in Table 1 from the Plan, kidney disease contributes to major medical costs in the United States, so factors reducing time to recovery, are beneficial to society.
Equally significant, is the fact that the number of cases of acute renal failure is growing at a rate of 9% per year (NIH, 1995) and this high rate of growth is expected to continue. A reason given for this rise in the incidence of renal failure is that "sicker" patients with a high risk of renal failure are surviving longer.
1. Older patients, who have a significantly higher incidence of acute renal failure (e.g., patients over 65 are 5 times more likely to be hospitalized for acute renal failure than those ages 45 to 64) are now surviving serious medical incidents (e.g., heart attack, stroke) as well as complicated surgery. Improved hospital intensive care units with more sophisticated monitoring and life support systems also aid in keeping "sicker" patients alive. In addition improved therapeutic agents for treating cancer and life-threatening infections are often nephrotoxic.
2. Neonates, who have an extremely high risk of kidney failure are also surviving at shorter terms and at significantly lower birth weights. Such infants formerly had difficulties overcoming severe lung and heart problems, but these problems can now be successfully treated with improved drugs and techniques, particularly in specialized neonatal intensive care units.
Because these advances in treatment modalities are expected to continue and even accelerate, it is likely that the number of cases of acute renal failure will continue to increase, perhaps at an even faster rate.
At the present time no real "cure" exists for acute renal failure. The current method of treatment is to "rest" the kidney by performing dialysis to correct metabolic imbalances and wait for kidney function to return spontaneously.
Dialysis is a technique in which impurities and toxins from the blood, that are normally cleared through the kidneys are artificially removed through an extra-corporeal circuit and filter (hemodialysis) or through the peritoneal membrane. By removing such impurities the life threatening metabolic imbalances resulting from kidney failure can be corrected and the patient stabilized.
Mortality rates resulting from a patient's developing acute renal failure are extremely high. A recent study (Levy et al., 1996) that analyzed the effect of acute renal failure on patient mortality cites such rates as ranging from 42% to 88% based on 18 previously published reports. These rates have remained essentially unchanged since the early 1950's. In the 1996 study itself the mortality rate for hospitalized patients who developed acute renal failure was 5 times higher compared to similar patients without renal failure (34% vs. 7%).
A key finding of this study is that "acute renal failure appears to increase the risk of developing severe non-renal complications that lead to death and should not be regarded as a treatable complication of serious illness." Thus it appears that the rapid reversal of acute renal failure can significantly reduce the risk of mortality in patients who also frequently have complicated clinical courses by preventing the development of severe and often fatal non-renal complications.
It has long been known that the kidney is one of the few human organs that has an ability to repair itself after injury. Even in cases where the kidney has been irreversibly damaged, and there is extensive necrosis of kidney cells, strong evidence exists that some new cell growth occurs.
It has been proposed that growth factors are a therapeutic approach to stimulate or augment the regenerative process in the injured kidney and thereby reduce the severity and shorten the course of acute renal failure. The use of growth factors as a treatment for acute renal failure was first proposed by Toback (1984). However, finding suitable growth factors proved difficult. The rationale for this strategy was subsequently expanded after several specific growth factor proteins were identified (Mendley and Toback, 1989; Toback 1992 a and b). However, no factors have yet been confirmed as useful in treating humans.
Growth factors acting in vivo to stimulate proliferation and migration of noninjured tubular cells in the kidney, and possibly to facilitate recovery of sublethally-injured cells as well, would be beneficial. A specific growth factor could be used in combination with sufficient nutrients, calories, and dialytic therapy to increase survival of patients with renal problems. For example, administration of growth factors could (1) increase positive outcomes in patients with cadaveric renal transplants, a situation in which acute renal failure is associated with increased rejection, (2) shorten the duration of acute renal failure which would increase patient survival, and (3) reduce the number of days required for hemodialysis treatment during the renal failure syndrome.
Autocrine growth factors are produced locally by the same cells on which they act. They appear to be produced in response to a stimulating event such as cell injury. Moreover, they are produced in extremely small quantities and may exist at detectable levels for only a short time. Consequently, they have been quite difficult to isolate and identify.
Two other types of growth factors--paracrine and endocrine--both appear to have some role in stimulating kidney cell growth. Paracrine factors act on adjacent cells (rather than on themselves) while endocrine factors are produced in one cell and transported (e.g., by the blood stream) to act on another, distant cell. Several of these types of factors, which are typically produced in larger quantities, and have a longer "half life" than some autocrine factors, have been discovered, and their cDNAs identified.
Animal and Clinical Studies
Several growth factors have been studied in an acute renal failure rat model to determine their efficacy in speeding recovery. The results of these studies give encouraging support to the theory that growth factors may play a major role in accelerating kidney repair. Three of the most important of these are:
1. Epidermal growth factor (EGF) The EGF factor has been reported to accelerate recovery in rats with acute renal failure. However, it was noted that EGF also mobilizes calcium from bone, which is a serious side effect that will likely prohibit its use in humans.
2. Insulin like growth factor -1 (IGF-1). Several studies in the rat model confirm that this factor is indeed efficacious. However, in two clinical studies in humans IGF-1 did not appear to have any substantial effect in speeding a patient's recovery from acute renal failure.
3. Osteogenic protein -1 (OP-1) is a bone growth factor already approved for human use in repairing bone, cartilage, and eye tissue. Although OP-1 may play a key role in the embryonic development of human kidneys, it is not clear how it works to help repair adult kidney cells. It is possible that OP-1 and other autocrine kidney growth factors together could have complementary mechanisms of action.
Autocrine Kidney Growth Factors
Although the animal study results on the previously identified growth factors are encouraging, none of these factors are used clinically at present. Of particular note is that the kidney messenger RNA for the three growth factors described above--EGF, IGF-1 and OP-1-actually decreases in the kidneys during acute renal failure. Logically, if a growth factor is to be effective in repairing injury and reversing acute renal failure, its levels would be expected to increase during this clinical event.
Some of the factors already identified are released by kidney epithelial cells and are capable of stimulating growth of the cells in an autocrine manner. For example, monkey kidney (BSC-1) cells respond to culture medium with a reduced concentration of potassium by releasing the "Low Potassium Growth Factor," and respond to a reduced concentration of sodium by releasing the "Low Sodium Growth Factor" (Mordan and Toback, 1984; Walsh-Reitz et al., 1986; Toback et al. 1992b and 1995).
A significant need exists for new therapeutic approaches to "cure," or at a minimum, speed the reversal of acute renal failure.